Search

Preclinical and clinical findings suggest sexual dimorphism in cardiotoxicity induced by a chemotherapeutic drug, doxorubicin (DOX). However, molecular alterations leading to sex‐related differential vulnerability of heart to DOX toxicity are not fully explored. In the present study, RNA sequencing in hearts of B6C3F1 mice indicated more differentially expressed genes in males than females (224 vs. 19; ≥1.5‐fold, False Discovery Rate [FDR] < 0.05) at 1 week after receiving 24 mg/kg total cumulative DOX dose that induced cardiac lesions only in males. Pathway analysis further revealed probable inactivation of cardiac apelin fibroblast signaling pathway (p = 0.00004) only in DOX‐treated male mice that showed ≥1.25‐fold downregulation in the transcript and protein levels of the apelin receptor, APJ. In hearts of DOX‐treated females, the transcript levels of apelin (1.24‐fold) and APJ (1.47‐fold) were significantly (p < 0.05) increased compared to saline‐treated controls. Sex‐related differential DOX effect was also observed on molecular targets downstream of the apelin‐APJ pathway in cardiac fibroblasts and cardiomyocytes. In cardiac fibroblasts, upregulation of Tgf‐β2, Ctgf, Sphk1, Serpine1, and Timp1 (fibrosis; FDR < 0.05) in DOX‐treated males and upregulation of only Tgf‐β2 and Timp1 (p < 0.05) in females suggested a greater DOX toxicity in hearts of males than females. Additionally, Ryr2 and Serca2 (calcium handling; FDR < 0.05) were downregulated in conjunction with 1.35‐fold upregulation of Casp12 (sarcoplasmic reticulum‐mediated apoptosis; FDR < 0.05) in DOX‐treated male mice. Drug effect on the transcript level of these genes was less severe in female hearts. Collectively, these data suggest a likely role of the apelin‐APJ axis in sex‐related differential DOX‐induced cardiotoxicity in our mouse model. RNA sequencing in mouse hearts 1‐week after 24 mg/kg cumulative doxorubicin dose suggested a potential role of the apelin‐APJ pathway in sex‐related differential DOX‐induced cardiotoxicity. In males, the apelin receptor, APJ, was downregulated, whereas apelin and APJ were upregulated in females compared to saline‐treated counterparts. Downstream alterations were also seen, including significantly altered expression of Tgf‐β2, Sphk1, Serpine1, Ctgf, and Timp1 (fibrosis) in cardiac fibroblasts and Ryr2 and Serca2 (Ca2+ homeostasis) in cardiomyocytes with greater effects in males than females. [ABSTRACT FROM AUTHOR]

Subclinical cardiotoxicity at low total cumulative doxorubicin (DOX) doses can manifest into cardiomyopathy in long‐term cancer survivors. However, the underlying mechanisms are poorly understood. In male B6C3F1 mice, assessment of cardiac function by echocardiography was performed at 1, 4, 10, 17, and 24 weeks after exposure to 6, 9, 12, and 24 mg/kg total cumulative DOX doses or saline (SAL) to monitor development of delayed‐onset cardiotoxicity. The 6‐ or 9‐mg/kg total cumulative doses resulted in a significant time‐dependent decline in systolic function (left ventricular ejection fraction (LVEF) and fractional shortening (FS)) during the 24‐week recovery although there was not a significant alteration in % LVEF or % FS at any specific time point during the recovery. A significant decline in systolic function was elicited by the cardiotoxic cumulative DOX dose (24 mg/kg) during the 4‐ to 24‐week period after treatment compared to SAL‐treated counterparts. At 24 weeks after DOX treatment, a significant dose‐related decrease in the expression of genes and proteins involved in sarcoplasmic reticulum (SR) calcium homeostasis (Ryr2 and Serca2) was associated with a dose‐related increase in the transcript level of Casp12 (SR‐specific apoptosis) in hearts. These mice also showed enhanced apoptotic activity in hearts indicated by a significant dose‐related elevation in the number of apoptotic cardiomyocytes compared to SAL‐treated counterparts. These findings collectively suggest that a steady decline in SR calcium handling and apoptosis might be involved in the development of subclinical cardiotoxicity that can evolve into irreversible cardiomyopathy later in life. Subclinical cardiotoxicity elicited by low total cumulative doxorubicin (DOX) doses can occur years after treatment in cancer patients. In male B6C3F1 mice, a progressive deterioration in heart function measured by echocardiography was evidenced by a significant time‐dependent decline in systolic function during 24 weeks after treatment with 6‐ or 9‐mg/kg total cumulative DOX doses. A significant dose‐related downregulation of Ryr2 and Serca2 and increased number of apoptotic cardiomyocytes at 24 weeks after treatment may underlie delayed‐onset subclinical cardiac dysfunction. [ABSTRACT FROM AUTHOR]

The imbalance of testosterone to estradiol ratio has been related to the development of prostate diseases. Although rat models of prostate diseases induced by endocrine-disrupting chemicals (EDCs) and/or hormone exposure are commonly used to analyze gene expression profiles in the prostate, most studies utilize a single endpoint. In this study, microarray analysis was used for gene expression profiling in rat prostate tissue after exposure to EDCs and sex hormones over multiple time points (prepubertal through adulthood). We used dorsolateral prostate tissues from Sprague-Dawley rats (male offspring) and postnatally administered estradiol benzoate (EB) on postnatal days (PNDs) 1, 3, and 5, followed by treatment with additional hormones [estradiol (E) and testosterone (T)] on PNDs 90-200, as described by Ho et al. Microarray analysis was performed for gene expression profiling in the dorsolateral prostate, and the results were validated via qRT-PCR. The genes in cytokine-cytokine receptor interaction, cell adhesion molecules, and chemokines were upregulated in the EB+T+E group on PNDs 145 and 200. Moreover, early-stage downregulation of anti-inflammatory gene: bone morphogenetic protein 7 gene was observed. These findings suggest that exposure to EB, T, and E activates multiple pathways and simultaneously downregulates anti-inflammatory genes. Interestingly, these genes are reportedly expressed in prostate cancer tissues/cell lines. Further studies are required to elucidate the mechanism, including analyses using human prostate tissues. [ABSTRACT FROM AUTHOR]

The present study aimed to identify molecular markers of early stages of cardiotoxicity induced by a potent chemotherapeutic agent, doxorubicin (DOX). Male B6C3F1 mice were dosed with 3 mg kg−1 DOX or saline via tail vein weekly for 2, 3, 4, 6 or 8 weeks (cumulative DOX doses of 6, 9, 12, 18 or 24 mg kg−1, respectively) and euthanized a week after the last dose. Mass spectrometry-based and nuclear magnetic resonance spectrometry-based metabolic profiling were employed to identify initial biomarkers of cardiotoxicity before myocardial injury and cardiac pathology, which were not noted until after the 18 and 24 mg kg−1 cumulative doses, respectively. After a cumulative dose of 6 mg kg−1, 18 amino acids and four biogenic amines (acetylornithine, kynurenine, putrescine and serotonin) were significantly increased in cardiac tissue; 16 amino acids and two biogenic amines (acetylornithine and hydroxyproline) were significantly altered in plasma. In addition, 16 acylcarnitines were significantly increased in plasma and five were significantly decreased in cardiac tissue compared to saline-treated controls. Plasma lactate and succinate, involved in the Krebs cycle, were significantly altered after a cumulative dose of 6 mg kg−1. A few metabolites remained altered at higher cumulative DOX doses, which could partly indicate a transition from injury processes at 2 weeks to repair processes with additional injury happening concurrently before myocardial injury at 8 weeks. These altered metabolic profiles in mouse heart and plasma during the initial stages of injury progression due to DOX treatment may suggest these metabolites as candidate early biomarkers of cardiotoxicity. Published 2016. This article is a U.S. Government work and is in the public domain in the USA [ABSTRACT FROM AUTHOR]

Abstract: The aim of this study is to predict dermal permeability of four phenolic biocides in four different formulations using a linear solvation energy relationship (LSER) approach, with a calibrated flow through diffusion cell system. Mathematical descriptors were determined in the laboratory, by mathematical computations, and by statistical methods. Infinite doses of 4 biocides and 25 probe chemicals in water, 17% methanol and 2 commercial metalworking fluids namely Astrocut–C® and Tapfree 2® were applied to porcine skin flow through diffusion cells. The strength coefficients for the 25 probe compounds for each system were determined from multiple linear regression analysis and plugged into the Abraham''s LSER equation to predict permeability values for biocides. Biocide permeability significantly decreased in methanol, Astrocut–C® and Tapfree 2® when compared to water. The strength coefficients revealed that hydrophobicity played an important role in explaining the reduced permeability in vehicles compared to water. This finding is important for selection of biocides and cutting fluids formulation. The R 2 between experimental and predicted logKp of probe solutes for water, methanol, Astrocut–C® and Tapfree 2® were 0.70, 0.78, 0.89 and 0.84, respectively. In conclusion, the LSER approach adequately predicted the dermal permeability of four biocides in commercial cutting fluids and also shed light on the chemical interactions resulting in reduced permeability. [Copyright &y& Elsevier]

Cardiotoxicity is a serious adverse effect of doxorubicin (DOX) treatment in cancer patients. Currently, there is a lack of sensitive biomarkers to predict the risk of DOX-induced cardiotoxicity. Using SOMAmer-based proteomic technology, 1129 proteins were profiled to identify potential early biomarkers of cardiotoxicity in plasma from male B6C3F 1 mice given a weekly intravenous dose of 3 mg/kg DOX or saline (SAL) for 2, 3, 4, 6, or 8 weeks (6, 9, 12, 18, or 24 mg/kg cumulative DOX doses, respectively). Also, a group of mice received the cardio-protectant, dexrazoxane (DXZ; 60 mg/kg; intraperitoneal) 30 min before a weekly DOX or SAL dose. Proteomic analysis in plasma collected a week after the last dose showed a significant ≥1.2-fold change in level of 18 proteins in DOX-treated mice compared to SAL-treated counterparts during 8-week exposure. Of these, neurogenic locus notch homolog protein 1 (NOTCH1), von Willebrand factor (vWF), mitochondrial glutamate carrier 2, Wnt inhibitory factor 1, legumain, and mannan-binding lectin serine protease 1 were increased in plasma at 6 mg/kg cumulative DOX dose, prior to the release of myocardial injury marker, cardiac troponin I at 12 mg/kg and higher cumulative doses. These six proteins also remained significantly elevated following myocardial injury or pathology at 24 mg/kg. Pretreatment of mice with DXZ significantly attenuated DOX-induced elevated levels of only NOTCH1 and vWF with mitigation of cardiotoxicity. This suggests NOTCH1 and vWF as candidate early biomarkers of DOX cardiotoxicity, which may help in addressing a clinically important question of identifying cancer patients at risk for cardiotoxicity., (Published by Elsevier Inc.)

Sex is a risk factor for development of cardiotoxicity, induced by the anti-cancer drug, doxorubicin (DOX), in humans. To explore potential mechanisms underlying differential susceptibility to DOX between sexes, 8-week old male and female B6C3F 1 mice were dosed with 3mg/kg body weight DOX or an equivalent volume of saline via tail vein once a week for 6, 7, 8, and 9 consecutive weeks, resulting in 18, 21, 24, and 27mg/kg cumulative DOX doses, respectively. At necropsy, one week after each consecutive final dose, the extent of myocardial injury was greater in male mice compared to females as indicated by higher plasma concentrations of cardiac troponin T at all cumulative DOX doses with statistically significant differences between sexes at the 21 and 24mg/kg cumulative doses. A greater susceptibility to DOX in male mice was further confirmed by the presence of cytoplasmic vacuolization in cardiomyocytes, with left atrium being more vulnerable to DOX cardiotoxicity. The number of TUNEL-positive cardiomyocytes was mostly higher in DOX-treated male mice compared to female counterparts, showing a statistically significant sex-related difference only in left atrium at 21mg/kg cumulative dose. DOX-treated male mice also had an increased number of γ-H2A.X-positive (measure of DNA double-strand breaks) cardiomyocytes compared to female counterparts with a significant sex effect in the ventricle at 27mg/kg cumulative dose and right atrium at 21 and 27mg/kg cumulative doses. This newly established mouse model provides a means to identify biomarkers and access potential mechanisms underlying sex-related differences in DOX-induced cardiotoxicity., (Published by Elsevier Inc.)